Safety and efficacy of high-protein diets for weight loss

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Proceedings of the Nutrition Society (2012), 71, 339–349                                                          doi:10.1017/S0029665112000122
                                       g The Author 2012 First published online 8 March 2012

                                                  A satellite symposium co-hosted by the University of Aberdeen Rowett Institute of Nutrition and Health was held at
                                                                                       the University of Reading on 4 July 2011

                                               Satellite Symposium: Industry and academic partnerships for developing
                                                                     health-improving products*

                                                        Safety and efficacy of high-protein diets for weight loss

                                                                                               Alexandra M. Johnstone
                                               Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Aberdeen AB21 9SB, UK
Proceedings of the Nutrition Society

                                                              Dietary strategies that can help reduce hunger and promote fullness are beneficial for weight
                                                              control, since these are major limiting factors for success. High-protein (HP) diets, specifically
                                                              those that maintain the absolute number of grams ingested, while reducing energy, are a pop-
                                                              ular strategy for weight loss (WL) due to the effects of protein-induced satiety to control
                                                              hunger. Nonetheless, both the safety and efficacy of HP WL diets have been questioned, par-
                                                              ticularly in combination with low-carbohydrate advice. Nonetheless, for short-to-medium-term
                                                              intervention studies (over several months), increasing the energetic contribution of protein does
                                                              appear effective. The effects of HP diets on appetite, bone health, renal function, blood pres-
                                                              sure, cardiovascular bio-markers, antioxidant status, gut health and psychological function are
                                                              discussed. Further research is warranted to validate the physiological effects of HP diets over
                                                              longer periods of time, including studies that modify the quality of macronutrients (i.e. the type
                                                              of carbohydrate, fat and protein) and the interaction with other interventions (e.g. exercise and
                                                              dietary supplements).

                                                                    Weight loss: Body composition: Metabolic profile: High-protein diet: Appetite

                                                        What is a high-protein diet?                                intake is reduced, with only a 20 % increase in the actual
                                                                                                                    amount (g) of protein. The guidelines from the Institute of
                                       An important factor to consider is the definition of a ‘high-                Medicine allow for the inclusion of higher amounts of
                                       protein (HP) diet’, as there are several ways to consider the                protein than previously recommended in a healthy diet(4).
                                       protein content of a diet. The composition of the diet can                   This Institute concluded that there is no clear evidence that
                                       be determined as the absolute amount of the protein                          an HP intake increases the risk of renal stones, osteo-
                                       (grams), the % of total energy as protein or the amount of                   porosis, cancer or CVD. Thus, the acceptable protein dis-
                                       protein ingested per kg body weight. Normal protein intake                   tribution for maintenance requirements was set to 5–20%
                                       in the UK is approximately 16% of energy intake(1) for a                     of energy for children aged 1–3 years, 10–30 % for chil-
                                       sedentary adult, which is approximately 64–88 g/d at                         dren aged 3–18 years and 10–35 % for adults. It is not clear
                                       energy balance for females and males, respectively. There                    as to how much protein is required to maximise protein-
                                       is no general consensus as to what a ‘high’-protein diet is:                 induced satiety for energy restriction and WL or whether
                                       the food industry use the term ‘protein-enriched’ for 20 %                   there is a relationship with the energy density of the diet.
                                       protein from energy. The HP diets reported for weight loss                      Both the safety(5) and efficacy(5) of HP WL diets
                                       (WL) studies often include 30% of energy intake as pro-                      have been questioned, particularly in combination with
                                       tein. There are many variants such as the Zone diet(2) and                   low-carbohydrate advice(6). Low-carbohydrate or very low-
                                       the CSIRO diet(3). In general, protein as a percentage of                    carbohydrate diets are described as ketogenic diets when
                                       energy is doubled from 15 to 30%. Note, this does not                        carbohydrate intake is reduced to about 20 g/d to invoke
                                       mean that absolute protein intake (g) is doubled, as energy                  dietary ketosis, the production of the ketone bodies. These

                                       Abbreviations: eGFR, estimated glomerular filtration rate; GI, glycaemic index; HC, high carbohydrate; HP, high protein; WL, weight loss.
                                       Corresponding author: Dr Alex Johnstone, fax + 44 1224 716686, email Alex.Johnstone@abdn.ac.uk
                                       *This symposium was industrially sponsored and was supplementary to the Nutrition Society Summer meeting.

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340                                                     A. M. Johnstone

                                       are b-hydroxybutyrate and acetoacetate (known collec-             alcohol. Included in the ‘processed foods’ is increased
                                       tively as ketone bodies), and are produced by the liver as        meat consumption. In developing countries, meat con-
                                       an alternative fuel for the brain. The diet mimics aspects of     sumption (estimated from carcass weights) is estimated
                                       starvation by forcing the body to burn fats rather than           to have nearly trebled in intake per year from 1962 to
                                       carbohydrates. Normally, the carbohydrates contained in           2003, and estimated to rise to 2030(13,14). At least in the
                                       food are converted into glucose, which is then transported        developed world, we currently eat in excess of our energy
                                       around the body and is particularly important in                  requirements, contributing to the overweight and obesity
                                       fuelling brain function. However, if there is very little         problem. Over-eating energy will often mean over con-
                                       carbohydrate in the diet, the liver converts fat into fatty       suming protein as an absolute amount (g). This will not
                                       acids and ketone bodies. The ketone bodies pass into              improve satiety feedback to curb consumption. In the
                                       the brain and replace glucose as an energy source. An             context of HP diets for WL, this can be considered a diet
                                       elevated level of ketone bodies in the blood produces a           that contains greater proportion of protein (%) from
                                       state known as ketosis. One such low-carbohydrate diet            energy. Increasing protein % will invoke an appetite
                                       example is the ‘Atkins dietary revolution’(6). The authors(7)     response to decrease ad libitum energy intake. From an
                                       consider that HP, low-carbohydrate diets (ketogenic diets)        environmental point of view, ever-increasing meat and
                                       do not offer much advantage over HP, moderate-                    dairy consumption has implications for environmental
                                       carbohydrate diets in terms of appetite control or metabolic      issues such as greenhouse gas emissions, climate
                                       advantage and that their own work on gut health supports          change and land use. These issues of climate change,
Proceedings of the Nutrition Society

                                       the notion of maintaining carbohydrate for a healthy gut          conservation and sustainability have recently been dis-
                                       microflora(8).                                                    cussed in a commissioned report for the World Wildlife
                                          The World Cancer Research Fund UK recommends                   Fund (Livewell: a balance of healthy and sustainable food
                                       limiting consumption of red meat and avoiding processed           choices, 2011)(15).
                                       meats to reduce cancer risk when eating for ‘healthy eat-            Relatively little is known about the influence of chronic
                                       ing’ at maintenance requirements; specifically, to eat not        (excess) oral protein intake on kidney function, since most
                                       more than 500 g (cooked weight) per week of red meats,            studies only examine the effect of a short-term change in
                                       such as beef, pork and lamb, and avoid processed meats            protein intake. One special interest group in this respect is
                                       such as ham, bacon, salami, hot dogs and some sausages(9).        body builders, because increased muscle size and definition
                                       The World Cancer Research Fund report recommended                 are important as judged by appearance in this competitive
                                       limiting ‘intake of red meat to less than 80 g daily’.            sport. Body builders are advised to consume 55–60 %
                                       The UK Reference Nutrient Intake for adult males                  carbohydrate, 25–30 % protein and 15–20 % fat, for both
                                       (19–50 years) is 55.5 g protein and for females 45.0 g (note      the off-season and pre-contest phases(16). Apart from the
                                       not meat intake). The upper recommendation is not to eat          obvious pharmacological con-founders that may influence
                                       more than 1.5 g protein kg per d for the general public not       metabolism, there are a couple of relevant publications that
                                       engaged in strenuous physical activity(10). A WHO con-            have examined nutritional intake in this unique sports
                                       sensus document stated that, ‘consumption of red meat is          group. Poortmans and Dellalieux(17) investigated body
                                       probably associated with increased colorectal cancer risk’,       builders and other well-trained athletes using a 7-d nutri-
                                       but also stated that epidemiological studies on meat and          tion record analysis as well as blood sample and urine
                                       colorectal cancer risk are not consistent(11). Both the Chief     collection to determine the potential renal consequences of
                                       Medical Officer’s Committee on Medical Aspects of                 an HP intake. The data revealed that despite higher plasma
                                       Food(12) and World Cancer Research Fund reports made              concentration of uric acid and Ca, the body builders had
                                       dietary recommendations based on their qualitative assess-        renal clearances of creatinine, urea and albumin that were
                                       ments of the epidemiological literature. The Chief Medical        within the normal range. The N balance for both groups
                                       Officer’s Committee on Medical Aspects of Food(12) report         became positive when daily protein intake exceeded
                                       on ‘Nutritional aspects of cancer’ targeted at the population     1.26 g/kg but there were no correlations between protein
                                       of the United Kingdom, advised that consumption of red            intake and creatinine clearance, albumin excretion rate and
                                       and processed meat for those consuming population average         Ca excretion rate. They concluded that protein intake under
                                       levels (approximately 90 g/d for the United Kingdom popu-         2.8 g/kg does not impair renal function in well-trained
                                       lation) should not rise for maintenance requirements.             athletes as indicated by the measures of renal function
                                          Protein intake can be considered not only at an indivi-        utilised. Similarly, Brandle et al.(18) included eighty-eight
                                       dual dietary requirement level but also at a population           healthy volunteers with normal renal function (thirty-two
                                       level. Although there are still considerable differences          vegetarians, twelve body builders with no supplementary
                                       between developing and developed countries, increases in          protein concentrates, twenty-eight body builders with sup-
                                       income and advances in agriculture have enabled us to             plementary protein concentrates and sixteen subjects with
                                       enrich and diversify diets over the last 150 years. With          no special diet), studied for 4 months. N excretion rates
                                       higher disposable incomes and urbanisation, people have           ranged between 2.66 and 33.93 g/d, reflecting a daily pro-
                                       moved away from mainly plant-based diets of varying               tein consumption between 17 and 212 g/d or 0.29 and
                                       nutritional quality (based on indigenous staple grains or         2.6 g/kg body weight per d, respectively. Their investiga-
                                       starchy roots, locally grown vegetables, other vegetables         tion indicated that chronic oral protein intake of widely
                                       and fruits and limited foods of animal origin) towards more       varying amounts of protein is a crucial control variable for
                                       varied diets that include more processed food, more foods         the glomerular filtration rate in subjects with healthy kid-
                                       of animal origin, more added sugar and fat, and often more        neys. They suggested that these changes reflect in part

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Safety and efficacy of high-protein diets                                                                  341

                                       structural changes of the glomerulus and tubules due to                   Due et al.(25) report substantially greater compliance in
                                       chronic protein intake, indicating adaptive physiological                 subjects consuming a higher-protein diet (25 % protein of
                                       mechanisms to deal with the HP intake.                                    energy) with an 8% drop out rate compared with subjects
                                                                                                                 on a low-protein diet (12 % energy) with a 28% drop-out.
                                                                                                                 Indeed, the recent extensive EU-wide Diogenes trial(28)
                                               Efficacy of high-protein weight loss diets                        examined low-protein and HP diets with low and high
                                                                                                                 glycaemic-index (GI) components. Specifically, of the five
                                        Short-term body weight and body composition changes
                                                                                                                 popular diet types tested, a HP, low GI diet provided the
                                       Free-living subjects feeding ad libitum from HP diets                     greatest opportunity for WL maintenance. The dropout rate
                                       show a WL of about 1 kg a week(19,20) which is consistent                 was lower in the groups that were assigned to HP diets and
                                       with current dietary advice on rate of WL from health                     the groups that were assigned to low-GI diets than in the
                                       professionals (e.g. British Dietetic Association, http://                 group that was assigned to the diet that was low in protein
                                       www.bda.uk.com). As a result of the WL, there are sig-                    and had a high GI (26.4 and 25.6%, respectively, v.
                                       nificant improvements in body composition, blood pressure                 37.4%; P = 0.02 and P = 0.01 for the HP groups, low-GI
                                       and bio-markers of health. The reduction in body fat mass                 groups and LP-low-GI groups, respectively). HP diets have
                                       (kg) and maintenance of lean mass (kg) during energy                      beneficial effects on body fat regulation, but the difference
                                       restriction and WL has been reported previously by other                  in effect of various types of protein is not known(29). Ani-
                                                                                                                 mal proteins, especially those from dairy, seem to support
Proceedings of the Nutrition Society

                                       authors and, in part, is related to the protein-enriched
                                       composition of the diet(21). In a recent meta regression,                 better muscle protein synthesis during weight reduction
                                       Krieger et al.(22) and Clifton et al.(23) examined eighty-                regimes in comparison with plant proteins because they
                                       seven short-term studies and found that protein intakes of                contain all essential amino acids and are generally well
                                       > 1.05 g/kg of actual (rather than desirable body weight)                 digested. This could potentially enhance energy expendi-
                                       were associated with 0.6 kg better retention of lean mass,                ture, but no conclusion can be drawn from the scant evi-
                                       and in studies greater than 12 weeks in duration, this                    dence(29). Some studies, but not all, demonstrate a higher
                                       increased to 1.2 kg. In studies that used a carbohydrate                  satiating effect of whey and fish proteins than other protein
                                       intake of less than 35–41 % there was a 2 kg greater loss                 sources. The evidence from intervention studies comparing
                                       of fat mass, and this was accompanied by a 0.7 kg greater                 the effects of different protein sources on body weight is
                                       loss of lean mass. In studies of 12 weeks or more, this                   inconclusive(29). However, body composition was not
                                       increased to 5.6 and 1.7 kg, respectively. Several studies                evaluated precisely in these studies and the literature is still
                                       have also looked at body composition to test the hypothesis               incomplete (e.g. comparative data are missing for legumes
                                       that HP diets spare the lean body mass of those on energy                 and nuts). Protein intake enhances energy expenditure,
                                       restricted diets. Most found greater fat loss with the HP                 satiety and fat loss, but there is no clear evidence to indi-
                                       diets in comparison with the lower-protein diets, but fewer               cate whether there is a difference in the effect size depen-
                                       reported this to be statistically significant, probably a                 dent on the source of the protein, i.e. from animal- or
                                       function of body composition techniques, small study                      plant-based foods.
                                       sizes, and different applied definitions of ‘HP’. In general,
                                       it is accepted that a reduced carbohydrate, HP diet is
                                       associated with better fat loss and relatively less lean
                                       mass loss.
                                                                                                                          Follow-up of weight regain after high-protein
                                                                                                                                        weight loss diet
                                       Longer-term body weight and body composition changes
                                                                                                                 Several groups have examined this question with similar
                                       HP diets provide a potential benefit of improved com-                     outcomes. Lejeune et al.(30) report a 20% increase in pro-
                                       pliance during WL attempts. HP diets increase WL at                       tein intake (through an unmatched supplement) during
                                       12 months by about 3 kg compared with a high-                             weight maintenance after a 4-week WL period reduced
                                       carbohydrate (HC) diet(23). HC, low-fat diets have also                   weight regain by 50% over the subsequent 3 months.
                                       been shown to reduce weight at 12 months and have                         Claessens et al.(31) report a similar effect using a matched
                                       additional benefits of high-fibre intake and may reduce the               casein supplement over 12 weeks of weight maintenance,
                                       risk of diabetes(24). However, many people cannot maintain                which amounted to a differential of 2.2 kg fat. Layman
                                       these diets long term, so new solutions have been sought.                 et al.(32) found that a WL diet that had double the amount
                                       Surprisingly, trials have only appeared over recent                       of protein (1.6 v. 0.8 g/kg) led to better body composition
                                       years evaluating the effects of HP diets (including low-                  at both 4 and 12 months, especially in those participants
                                       carbohydrate versions), and these have shown WL benefits                  who lost more than 10% of their body weight over this
                                       at 6 months, which are lost by 12 months, indicating                      period. The recent ‘Diogenes’ trial provides data on the use
                                       similar poor compliance at this duration in all regimes(25).              of HP, low-GI diets for longer-term weight control. Spe-
                                       Patient diet choice will depend on dietary preferences and                cifically, weight regain was 0.93 kg less for the 773 parti-
                                       previous experiences with WL regimes. Groups consuming                    cipants on a HP diet than for those on a low-protein diet
                                       an HP, moderate-carbohydrate diet have an increased                       and 0.95 kg less in the groups on a low-GI diet compared
                                       likelihood of maintaining WL at 12 months and beyond,                     with those on a high-GI diet(28). These data support the
                                       with improvements in cardiovascular risk factors and                      use of HP, moderate-carbohydrate diets to achieve weight
                                       minimal risk of side effects(26,27). In a 12-month study,                 control.

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342                                                       A. M. Johnstone

                                        Potential side effects of high-protein weight loss diets              Bone health including osteoporosis. Millions of people
                                                                                                           are affected by osteoporosis, and women are four times
                                             Physiological and metabolic effects of high-protein
                                                                                                           more likely to suffer from this disease than men. Nutrition
                                                              weight loss diets
                                                                                                           plays an important role in both the prevention and the
                                          Appetite. Protein is more satiating than carbohydrate            pathogenesis of this chronic disease. Numerous studies
                                       and fat in the short term, over 24 h and in the long term(33).      have established that dietary Ca and vitamin D are critical
                                       In the short-term ‘fast’ proteins are more satiating than           nutrients for both accruing and maintaining skeletal mass.
                                       ‘slow’ proteins, and animal protein induces a higher ther-          In contrast, our understanding of how other dietary com-
                                       mogenesis than vegetable protein. In the longer term, the           ponents, such as protein, affect Ca homoeostasis and ske-
                                       higher post-absorptive satiety and thermogenesis are sus-           letal metabolism is limited(45). Our ability to accurately
                                       tained irrespective of the protein source(34). A variety of         measure changes in mineral homoeostasis has improved
                                       investigations have examined the effect of HP diets on              considerably in the last two decades. We now have better
                                       satiety. Typically, these studies presented one of several          ways to non-invasively assess rates of skeletal formation
                                       preloads with varying protein content to each subject on            and resorption, to quantify bone mass and to measure
                                       separate occasions in a cross-over design. For several hours        parathyroid activity. Using these tools, a more complex
                                       following the consumption of the preload, subjective sati-          picture of the effects of protein on Ca metabolism and
                                       ety ratings were measured repeatedly. Halton and Hu(34)             skeletal homoeostasis, particularly during low-dietary-
                                       summarised the main findings that of the fourteen studies           protein conditions, is beginning to emerge. Protein is
Proceedings of the Nutrition Society

                                       that compared HP to at least one other macronutrient, ele-          known to be essential to bone collagen synthesis, but it is
                                       ven found that the protein preload significantly increased          the Ca-wasting effect of a HP intake that remains at the
                                       subjective ratings of satiety. Other studies that have used         focal point of the debate. It has long been suggested that
                                       nose-clips (to reduce the impact of cephalic digestive cues         ‘too much’ protein (with no set definition of ‘too much’
                                       involved in early satiation) and liquid format(35,36) have not      given in the research literature) can have a negative effect
                                       found effects of HP meals suggesting a role in sensory              on bone health via increased calciuria. Research has shown
                                       characteristics in promoting satiety. The Maastricht lab has        that higher-protein diets do promote increased excretion of
                                       published many preloading studies that suggest that HP              Ca in the urine(46), which is taken to suggest adverse
                                       diets are more satiating in comparison with normal protein          effects on bone or to support the impact of bone loss. The
                                       meals, when fed at iso-energetic amounts(37–39).                    underlying premise is that an HP (especially animal pro-
                                          In summary, the evidence supports the conclusion that            tein) diet creates a higher acid load due to the high S
                                       meals higher in protein tend to increase satiety when               amino acid content, which cannot be neutralised by the
                                       compared with meals lower in protein, at least in the short         kidneys. To compensate, the body pulls Ca from the ske-
                                       term. Overall, the weight of evidence suggests that higher-         leton to balance the pH at the expense of the bone struc-
                                       protein intakes cause a decreased subsequent energy                 ture, and Ca is excreted in the urine. However, few studies
                                       intake, although the results are not entirely consistent. It        have supported this theory. The effect of dietary protein in
                                       appears that the closer the methodology is to real-life             the skeleton appears to be favourable to a small extent or,
                                       situations (real food v. liquid, sense of taste unaltered, free     at least, is not detrimental(47). A meta-analysis of rando-
                                       living v. whole body calorimeter), the more likely it is for        mised placebo-controlled trials indicated a positive
                                       protein to exert a significant decrease in subsequent energy        influence of all protein supplementation on lumbar spine
                                       intake. The majority of preload studies do find a decreased         bone mineral density. No significant effects were identified
                                       subsequent energy intake with a higher-protein preload.             for soya protein or milk basic protein on lumbar spine
                                       There are, however, some methodological issues concern-             bone mineral density(48). The positive effect(s) seems to
                                       ing this type of research. Satiety appears to be influenced         come from meat protein. For example, HP diets (parti-
                                       by a wide variety of factors including palatability, food           cularly those high in meat) have been shown to reduce the
                                       mass, energy density, fibre and GI. When using real foods,          risk of fractures in post-menospausal women(49). The effect
                                       it is difficult if not impossible to control for all of these       of high-animal protein intakes on Ca utilisation and bone
                                       influences at the same time while still delivering different        health has been recently reviewed(50). Increased potential
                                       amounts of protein(34).                                             renal acid load resulting from an HP intake (intake above
                                          The mechanisms promoting protein-induced satiety are             the current RDA of 0.8 g protein/kg body weight) has been
                                       not clear, but are likely to involve elevated amino acid            closely associated with increased urinary Ca excretion.
                                       concentrations, responses of anorexigenic hormones and              However, more recent findings do not support this
                                       protein-induced energy expenditure(38). Hunger, or at least         assumption. Neither whole body Ca balance, nor bone
                                       motivation to eat, is influenced by the palatability of the         status indicators, are negatively affected by the increased
                                       diet and this is an important determinant of intake(40) in          acid load. Indeed, beneficial effects of protein such as
                                       both short-term(41) and longer-term(42) studies. Indeed, it         increasing intestinal Ca absorption and circulating insulin-
                                       has been suggested that lower energy intakes during diet-           like growth factor-I while also lowering serum parathyroid
                                       ing are due to a lower palatability, or monotony, of the            hormone sufficiently offset any negative effects of the acid
                                       diet(43). In real life dieters may, by default, adopt more          load of protein on bone health. On the basis of recent
                                       limited diet choice because their nutritional knowledge is          findings(50), consuming protein (including that from meat)
                                       less. Were studies conducted over longer periods, palat-            higher than current RDA for protein is beneficial to Ca
                                       ability ratings may gradually decrease, as desire for even a        utilisation and bone health, especially in the elderly. A
                                       favourite food will wane if offered repeatedly(44).                 HP diet with adequate Ca and fruits and vegetables is

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Safety and efficacy of high-protein diets                                                                  343

                                       important for bone health and osteoporosis prevention(50).                1 year(65) indicated that there were no changes in either
                                       More research is required to resolve the protein debate.                  group in serum creatinine levels or estimated glomerular
                                       The protein intakes and balance of different protein sour-                filtration rate (eGFR), and urinary albumin excretion
                                       ces with a variety of different foods as indicated by the                 values remained in the normoalbuminuria range. This
                                       dietary guidelines represent appropriate dietary advice.                  study provides preliminary evidence that long-term WL
                                          Renal function. Valid concerns exist that HP diets may                 with a very-low-carbohydrate diet does not adversely
                                       induce clinically important alterations in renal function                 affect renal function compared with a HC diet in obese
                                       and health. HP consumption has been found, under various                  individuals with normal renal function. Similarly, inter-
                                       conditions, to lead to glomerular hyperfiltration and                     vention studies by Li et al.(66) and Skov et al.(60) also
                                       hyperaemia, acceleration of chronic kidney disease,                       indicate that protein-enriched meal replacements or an HP
                                       increased proteinuria, diuresis, natriuresis and kaliuresis               diet have no adverse outcomes on routine measures of
                                       with associated blood pressure changes, increased risk for                kidney function, up to 1 year. It may be that 12 months is
                                       nephrolithiasis and various metabolic alterations(51–53).                 not long enough to reveal adverse effects and further work
                                       Unfortunately, a comprehensive understanding of the                       may be necessary to examine this area.
                                       implications of HP diets is limited by the lack of a uni-                     Taken together, there is little evidence that HP diets
                                       versally accepted definition for HP intake, a paucity of                  pose a serious risk to kidney function in healthy popu-
                                       rigorous long-term human interventional studies that lead                 lations. More susceptible groups such as diabetics and
                                       to reliance on short-term or fairly circumstantial evidence,              those with existing renal disease should exercise more
Proceedings of the Nutrition Society

                                       and sparse data on the effects of HP consumption in obese                 caution with higher-protein intakes. This approach is sup-
                                       individuals. In addition, matters are further complicated                 ported by data from large-scale US studies. The Nurses’
                                       because the renal impact of HP diets for limited periods is               Health Study suggests that women with mild renal insuf-
                                       most likely different than that for more chronic consump-                 ficiency had a greater decline in renal function with a
                                       tion (see later). Nevertheless, although there are no clear               higher-protein intake(67). Those with normal renal function
                                       renal-related contraindications to HP diets in individuals                had no such decline. Recent work on an aging popula-
                                       with healthy kidney function, the theoretical risks should                tion(68), where renal function tends to decline (as indicated
                                       be reviewed carefully with the patient and clinician. In                  by reduced glomerular filtration rate), has investigated
                                       contrast, HP diets have the potential for significant harm in             whether dietary protein is associated with impaired renal
                                       individuals with chronic kidney disease and should be                     function. Data from two nested case–control studies within
                                       avoided if possible. Because chronic kidney disease is                    the Women’s Health Initiative Observational Study (n
                                       often a silent disease, all individuals should undergo a                  2419) were examined. Protein intake was estimated using
                                       screening for serum creatinine and a urinary dipstick test                an FFQ and eGFR from cystatin C. To account for the
                                       for proteinuria before the initiation of such a diet.                     original study designs, inverse probability weights were
                                          There has been some debate as to the safety of HP WL                   applied. Self-reported energy and protein were calibrated
                                       diets with regard to kidney function. In populations with                 using bio-markers of energy and protein intake. Associa-
                                       established renal disease, it has been shown that limiting                tions between protein intake and renal function were esti-
                                       protein to the RDA level may slow down the progression                    mated by weighted linear and logistic regression models.
                                       of disease(54). Whether or not HP (WL) diets adversely                    Average calibrated protein intake was 1.1 (SD 0.2) g/kg
                                       affect kidney function in healthy populations is not so                   body weight per d). Twelve per cent (n 292) of women had
                                       clear. An often-cited review paper, Eisenstein et al.(55)                 impaired renal function. The odds of impaired renal func-
                                       assessed the evidence and came to the conclusion that                     tion, defined as eGFR
344                                                      A. M. Johnstone

                                                 CVD risk factors including lipaemia                                                  Gut health

                                       Foods and diets high in protein may vary in saturated fat          There is epidemiological evidence for a protective effect
                                       and nutritional composition, and concerns have been raised         of fruits, vegetables and whole grains in almost all
                                       regarding the effect of HP diets on serum lipids and sub-          major cancers afflicting western society today including
                                       sequent CVD risk. There are limited epidemiological data           colorectal, breast, pancreatic, lung, stomach, oesophageal
                                       on HP intake and cardiovascular risk. A prospective cohort         and bladder cancer(83–86). Fruits and vegetables contain a
                                       study by Hu et al.(70) found that a higher protein intake          large variety of compounds such as dietary fibres, iso-
                                       (24 % of energy v. 15 % of energy) was associated with a           thiocyanates and polyphenols that possess antioxidant and
                                       decreased risk of CHD during 14 years of follow-up. Both           anti-inflammatory activities and are implicated in provid-
                                       animal and plant protein contributed to the lower risk. Risk       ing protection against cancer. Dietary fibres have a myriad
                                       was increased in the lowest quintiles of animal protein            of benefits in the colon such as diluting carcinogenic
                                       intake in women even after controlling for energy intake           compounds, accelerating stool transit time, increasing
                                       and traditional cardiovascular risk factors (median animal         production of beneficial fermentation products such as
                                       protein intake: lowest quintile 42.7 g/d, highest quintile         butyric acid and decreasing detrimental metabolites such as
                                       81.6 g/d). Iso et al.(71) found that very low levels of animal     N-nitrosamines, in addition to lowering colonic pH. All of
                                       protein intake were associated with an increased risk of           these effects have been proposed as being helpful in redu-
                                       haemorrhagic stroke. This is consistent with ecological            cing colon cancer risks. The current scientific evidence
Proceedings of the Nutrition Society

                                       data from Japan that suggests a low intake of protein              strongly suggests that it is not the consumption of one or
                                       increases the risk of intraparenchymal haemorrhagic                two varieties of vegetables and fruit that confer a benefit,
                                       stroke(72). Furthermore, in a meta-analysis of cross-sec-          but rather the intake of a wide variety of plant foods(87–89).
                                       tional investigations, Liu et al. found an inverse associa-        HP diets tend to have reduced carbohydrate content, in
                                       tion between dietary protein and blood pressure in both            the form of fruits, vegetables (if starchy foods are not
                                       sexes(73), although further studies will be needed to con-         adequately replaced by other types of low-carbohydrate-
                                       firm this association.                                             containing vegetables) and grains. This may theoretically
                                          Another area of controversy is the effect of HP diets           place an individual at an increased disease risk if such a
                                       on blood lipids. Farnsworth et al.(74) and Skov et al.(60)         diet is followed long term, and fruit and vegetable intakes
                                       found a decrease in TAG with higher-protein diets,                 remain low(90).
                                       whereas Parker et al.(75) found a lower LDL cholesterol               HP dieting is associated with increased consumption of
                                       level with a higher-protein diet. Finally, Wolfe found             meat, and red meat consumption has been linked to color-
                                       that the isoenergetic substitution of animal protein for           ectal cancer(91), but the evidence is not straightforward.
                                       carbohydrate raises HDL cholesterol and lowers TAG                 Increased intakes of meat and increased incidence of colo-
                                       levels in hypercolesterolaemic subjects(76) and normoli-           rectal cancers have been observed in some epidemiological
                                       paemic subjects(77). Jenkins et al.(78) conducted a 1 month        studies(92–94); however, this is specific to processed meat.
                                       study of a high wheat protein diet (27 %) compared with            It has been shown that a daily increase of 100 g of all
                                       a control diet (16 %) in hyperlipaemic subjects and                meat or red meat is associated with a 12–17 % increased
                                       found decreases in TAG and oxidised LDL cholesterol                risk of colorectal cancer(95). However, the WL induced by
                                       on the higher-protein diet. However, other investigators           dieting may counteract the observed epidemiological risks
                                       studying dietary protein and WL(79) found no significant           of increased meat consumption. Thus, the relationship
                                       differences in lipid profile between subjects consuming            between meat consumption and colorectal cancer risk
                                       higher- v. lower-protein diets. Although more research             remains controversial(96). Subsequent to the report of the
                                       is still needed in this area, it appears that higher-              National Academy of Sciences, ‘Diet and Health’(97),
                                       protein diets at the very least are not detrimental to blood       which implicated red meat as a causative factor in the
                                       lipids in the short term and the exchange of protein for           aetiology of colorectal cancer, two subsequent reports have
                                       carbohydrate may actually be beneficial for blood                  reviewed the epidemiological evidence on meat and col-
                                       lipids(80).                                                        orectal cancer risk(9,12). The report of the World Cancer
                                          The GI is a well-described property of carbohydrate-            Research Fund report concluded: ‘The evidence shows that
                                       containing foods that predicts the body’s blood glucose            red meat probably increases risk and processed meat pos-
                                       response(81). GI may be important in weight control efforts        sibly increases risk of colorectal cancer’(9). The report
                                       because it modulates hunger and satiety. Because protein           from Chief Medical Officer’s Committee on Medical
                                       has a minimal short-term effect on blood glucose in com-           Aspects of Food judged that ‘there is moderately consistent
                                       parison with carbohydrate, it can be used in metabolic             evidence from cohort studies of a positive association
                                       studies and WL efforts that strive to lower the GI of any          between the consumption of red or processed meat and risk
                                       particular diet. Although protein produces a lower blood           of colorectal cancer’(12). A WHO consensus statement
                                       glucose level than carbohydrate, it is known to produce an         reached a similar conclusion, stating that, ‘consumption of
                                       insulin response.                                                  red meat is probably associated with increased colorectal
                                          HP foods such as meat, poultry, seafood, eggs, seeds            cancer risk’, but also stated that epidemiological studies on
                                       and nuts are high in purines. Purines are broken down into         meat and colorectal cancer risk are not consistent(11). One
                                       uric acid, so excess consumption of these foods increases          US epidemiological study is often quoted, and reported
                                       uric acid levels and may cause gout in susceptible indivi-         high intake of red and processed meat in 1982 and again in
                                       duals(82).                                                         1992/1993 to be associated with higher risk of colon cancer

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Safety and efficacy of high-protein diets                                                                  345

                                       after adjusting for age and energy intake but not after                   on antioxidant status(20). These data suggest that an HP
                                       further adjustment for BMI, cigarette smoking and other                   WL diet does not impair plasma indices of antioxidant
                                       covariates(91). This suggests that obesity per se (excess                 status and bio-markers of cardiovascular and metabolic
                                       body fat) is also a factor. When long-term consumption                    health, at least within 4 weeks, in otherwise healthy obese
                                       was considered, persons in the highest tertile of consump-                subjects. The study compared HP low-carbohydrate and
                                       tion had higher risk of distal colon cancer associated with               HP, moderate-carbohydrate diets. In general, improve-
                                       processed meat and ratio of red meat to poultry and fish                  ments in bio-markers of health associated with WL were
                                       relative to those persons in the lowest tertile. Long-term                similar between the low-carbohydrate and moderate-
                                       consumption of poultry and fish was inversely associated                  carbohydrate diets. None of the subjects were deficient in
                                       with risk of both proximal and distal colon cancer. High                  vitamins, and although the diets were associated with a
                                       consumption of red meat was associated with higher risk of                small reduction in plasma concentrations of retinol, vita-
                                       rectal cancer. The authors concluded that prolonged high                  min E (a-tocopherol) and b-cryptoxanthin (P
346                                                          A. M. Johnstone

                                       profile, mood state and level of anxiety were measured in                      acids. Food and Nutrition Board, Institute of Medicine, The
                                       each test session. Consumption of the HP v. HC meal did                        National Academies, Washington DC, USA. J Am Diet
                                       not affect feelings of depression, tension, anger or anxiety.                  Assoc 102, 1621–1630.
                                       Cortisol levels did not differ between the four test-sessions            5.    St Jeor ST, Howard BV, Prewitt TE et al. (2001) Nutrition
                                                                                                                      Committee of the Council on Nutrition, Physical Activity,
                                       in men and women. Consumption of the test-meals
                                                                                                                      and Metabolism of the American Heart Association. Dietary
                                       increased cortisol levels in men in all conditions, and in                     protein and weight reduction: a statement for healthcare
                                       women only in the rest-protein and stress-protein condi-                       professionals from the Nutrition Committee of the Council
                                       tion. Men showed higher cortisol levels than women.                            on Nutrition, Physical Activity, and Metabolism of the
                                       Consumption of meals with different macronutrient con-                         American Heart Association. Circulation 104, 1869–1874.
                                       tents, i.e. HP v. HC, does not influence the physiological               6.    Astrup A (2005) The satiating power of protein – a key to
                                       and psychological response differentially. Men show a                          obesity prevention? Am J Clin Nutr 82, 1–2.
                                       higher meal-induced salivary cortisol response compared                  7.    Astrup A, Meinert Larsen T & Harper A (2004) Atkins and
                                       with women. Future research may focus on personalised                          other low-carbohydrate diets: hoax or an effective tool for
                                       nutrition and the role of diet composition and eating pat-                     weight loss? Lancet 364, 897–899.
                                                                                                                8.    Russell WR, Gratz SW, Duncan S et al. (2011) High pro-
                                       terns to enhance mood or compliance to WL strategies.
                                                                                                                      tein, reduced carbohydrate weight loss diets promote meta-
                                                                                                                      bolite profiles likely to be detrimental to colonic health. Am
                                                                                                                      J Clin Nutr 93, 1062–1072.
                                                                Conclusions
Proceedings of the Nutrition Society

                                                                                                                9.    World Cancer Research Fund (1997) Food, Nutrition, and
                                       With the ever-increasing obesity problem comes the search                      the Prevention of Cancer: a Global Perspective. Washing-
                                       for effective dietary strategies to (i) prevent weight gain,                   ton, DC: WCRF/AICR.
                                                                                                               10.    Department of Health (1991) Dietary Reference Values for
                                       (ii) promote WL, (iii) maintain a lower body weight. Sur-
                                                                                                                      Food, Energy and Nutrients for the United Kingdom,
                                       gical and pharmacological approaches for weight manage-                        pp. 78–84. London: HMSO.
                                       ment are only accessible for a small percentage of the                  11.    Scheppach W, Bingham S, Boutron-Ruault MC et al. (1999)
                                       obese population. Human subjects have a plentiful supply                       WHO consensus statement on the role of nutrition in col-
                                       of appealing, cheap, energy-dense foods and beverages that                     orectal cancer. Eur J Cancer Prev 8, 57–62.
                                       promote overconsumption and the challenge for public                    12.    Chief Medical Officer’s Committee on Medical Aspects of
                                       health sectors is how to encourage the population to make                      Food (1994) Nutritional Aspects of the Development of
                                       sensible food choices for safe and healthy eating. There is                    Cancer. No. 48. London: HMSO.
                                       no one dietary approach that will fix this complex problem,             13.    FAO (2006a) World agriculture: towards 2030/2050 Interim
                                       but HP diets seem to provide a tool to promote WL, in                          Report. Rome: FAO.
                                                                                                               14.    FAO (2006b) FAO statistical databases. Rome: FAO;
                                       healthy subjects. The benefits of WL need to be weighed
                                                                                                                      available at http://faostat.fao.org/default.aspx
                                       against the consequences of excess adiposity on health.                 15.    Livewell (2011) A balance of healthy and sustainable
                                       With larger EU-funded studies being published and more                         food choices. A Commissioned Report for World Wildlife
                                       work underway, the limitations and applications of HP                          Fund; available at http://assets.wwf.org.uk/downloads/
                                       diets for weight control will undoubtedly become clearer.                      livewell_report_jan11.pdf
                                                                                                               16.    Lambert CP, Frank LL & Evans WJ (2004) Macronutrient
                                                                                                                      considerations for the sport of bodybuilding. Sports Med 34,
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                                                                                                               17.    Poortmans JR & Dellalieux O (2000) Do regular high pro-
                                       The author has acted as a consultant for Marks and                             tein diets have potential health risks on kidney function in
                                       Spencer plc. The Rowett Institute is grateful for funding                      athletes? Int J Sport Nur Exerc Metab 10, 28–38.
                                       from the Scottish Government.                                           18.    Brandle E, Sieberth HG & Hautmann RE (1996) Effect of
                                                                                                                      chronic dietary protein intake on the renal function in
                                                                                                                      healthy subjects. Eur J Clin Nutr 50, 734–740.
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